Clinical study

A Randomized, Double-Blind, Multicenter, Placebo-Controlled, Parallel-Group Phase III Study to Evaluate the Efficacy, Tolerability and Safety of Intramuscular Injections of PLX-PAD for the Treatment of Subjects with Critical Limb Ischemia (CLI) with Minor Tissue Loss who are Unsuitable for Revascularization.

STUDY OBJECTIVES: The objective of the study is to evaluate the efficacy, tolerability and safety of local intramuscular (IM) injections of PLX-PAD in CLI subjects unsuitable for revascularization.

POPULATION: The study will be conducted in 246 subjects diagnosed with CLI with minor tissue loss (Rutherford Category 5) who are unsuitable for revascularization.

Survival analysis with variable follow up to enhance Powe r
Study end: 12 months after the actual/planned 1st treatment visit of the last randomized subject, or 36 months after actual/planned 1st treatment visit of the first randomized subject, the later of the two.
Each subject will be followed-up until the End of Study or until completing 36 months of follow-up, the earlier of the two (hence, range between 12 to 36 months).

Interim analysis
An efficacy interim analysis (IA) will be performed in support of a conditional marketing authorization application to the EMA (as per adaptive pathways approach).
IA will be performed at 12 months following the randomization of the last subject among the first 50% of the population planned to be recruited.
Efficacy will be judged based on primary or secondary efficacy endpoints.
Study will be completed for full approval.

Primary efficacy endpoint
Time (days) from randomization to occurrence of major amputation of the index leg or death - Amputation-free survival (AFS).

The principal analysis of the primary endpoint will use the ITT analysis set comprised of all randomized subjects (even if no study drug has been administered).

An effort to obtain the primary outcome data on major amputation and death for subjects who did not come to study visits will be made in order to reduce the need for imputation of missing data as requested by Regulators.

Secondary efficacy endpoints
Time (days) from randomization to first occurrence of any of the following single events:

Major amputation of the index leg.

Revascularization due to worsening of CLI in the index leg.

Doubling of total wound area from baseline in the index leg.

De novo gangrene in the index leg.

All-cause mortality.

Time (days) from randomization to major amputation of the index leg.

Proportion of subjects with complete wound healing in the index leg at 12 months.

Change from baseline in ischemic pain (NRS) at 6 months.

Time (days) from randomization to occurrence of death or adjudicated major amputation of the index leg.